1153-P: Sodium-Glucose Cotransporter-2 Inhibitors Increase Food Intake via a Mechanism That Acts on the Central Nervous System Involving Phosphorylation of Adenosine Monophosphate-Activated Protein Kinase in the Lateral Hypothalamus

Abstract

Sodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake. We administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. Bolus ICV SGLT2 inhibitor induced an increase in food intake. Tofogliflozin had the strongest effect among these drugs. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Intraperitoneal administration of liraglutide, a GLP-1 receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin. ICV tofogliflozin increased phosphorylation of AMPK in the lateral hypothalamus. In conclusion, SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area. Disclosure K. Takeda: None. H. Ono: None. T. Ohno: None. K. Yokote: None. Funding Japan Society for the Promotion of Science (15K09398, 18K08502, 20H00524); Japan Agency for Medical Research and Development (17GM5010002H0001, 18GM5010002H0002, 19GM5010002H0003, 20GM5010002H0004)